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Screenshot 2024-02-27 at 2.45.37 AM
Screenshot 2024-02-27 at 2.45.37 AM
LEARNING OBJECTIVES
EPIDEMIOLOGY
Most common systemic inflammatory disease Genetics
Prevalence: 1-2%
Occurrence:
●Any age but the frequency increases with age,
peaks between 30-50 years.
Also observed in both elderly Environment
PATHOPHYSIOLOGY
• Autoimmune disease
● Lack of differentiation between self and non-self tissues
● Destruction of synovial and connective tissues
• Pannus
● Inflamed, proliferating synovium
● Invades cartilage and bone surface joint destruction
● Characteristic of RA
PATHOPHSYIOLOGY(2)
PRO-INFLAMMATORY
LYMPHOCYTES
CYTOKINES
B Lymphocytes T Lymphocytes TNF α, IL-1, IL-6, IL-17
• Origin: bone marrow • Origin: thymus • Initiate and continue
• Produce rheumatoid factor • Produce cytokines and inflammatory process
and anticyclic citrullinated cytotoxins • Stimulate osteoclast
peptide • Further promote formation
• Attract neutrophils to sites inflammation and tissue • Suppress osteoblasts and
of injury destruction bone formation
• Act an APCs to stimulate • Stimulate macrophages to
T cells and activate the release prostaglandins and
immune process cytotoxins
APCs = antigen-presenting cells
All the major immunologic elements play fundamental roles in the initiation, propagation, and maintenance of the autoimmune process
of RA. It involves T and B lymphocytes, antigen-presenting cells (eg, B cells, macrophages, dendritic cells), and numerous cytokines.
Aberrant production and regulation of both pro-and anti-inflammatory cytokines and cytokine pathways are found in RA.
T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the Th1 CD4 cells. (T
helper 1 cells produce IL-2 and interferon gamma.) These cells may subsequently activate macrophages and other cell populations,
including synovial fibroblasts. The latter 2 populations are the main producers of the proinflammatory cytokines TNF-alpha and IL-1 that
appear to be the major driving forces of inflammation.
B cells are important in the pathologic process because they may serve as antigen-presenting cells and activated T cells, produce
numerous autoantibodies (eg, RF, to citrullinated proteins), and secrete cytokines.
Elimination of populations of B cells with monoclonal antibodies (eg, rituximab) offers another effective therapeutic option.
Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-a), interleukins IL-1, IL-6, IL-8
and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.
Synovial macrophages and dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the
production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes. Once
triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells
(mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). The disease progresses in concert with formation of granulation tissue
at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage.
Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and
evidence of joint destruction accrues. Although the articular structures are the primary sites, other tissues are also affected
PATHOPHSYIOLOGY(3)
Clinical presentation
• Extraarticular involvement
• Laboratory abnormalities
1- Most patients with the disease have an insidious onset. It may begin with systemic features, such as fever, malaise,
arthralgias, and weakness, before the appearance of overt joint inflammation and swelling.
2-A small percentage of patients (approximately 10) have an abrupt onset with the acute development of synovitis and extra-
articular manifestations. Spontaneous remission is uncommon, especially after the first 3-6 months.
3- Joint involvement is the characteristic feature of patients with RA. In general, the small joints of the hands and feet are
affected in a relatively symmetric distribution. Joints show inflammation with swelling, tenderness, warmth, and decreased
range of motion.
4- Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to the
following irreversible deformities:
A. ulnar deviation
B. boutonnière
C. swan-neck deformities
D. hammer toes, and occasionally joint ankylosis.
5- Other musculoskeletal manifestations include: Tenosynovitis, Tendon rupture commonly involving the 4th and 5th digital
extensor tendons at the wrist),Periarticular osteoporosis, generalized osteoporosis, systemic chronic inflammation,
immobilization-related changes or corticosteroid therapy, Carpal tunnel syndrome and Muscle atrophy from disuse.
6- Most commonly affected joints, in decreasing frequency are: 1-MCP 2- Wrist 3- PIP 4-Knee 5- MTP 6- Shoulder 7-Ankle
8-Cervical spine 9-Hip 10-Elbow 11-Temporomandibular.
Joint Involvement and radiographic changes
EXTRAARTICULAR INVOLVEMENT
• Skin manifestations
Subcutaneous nodules (Rheumatoid nodules), vasculitic lesions palpable purpura or skin ulceration
• Pulmonary complications
pleural effusions, interstitial fibrosis, nodules (Caplan syndrome), and bronchiolitis obliterans-organizing pneumonia.
• Cardiac involvement
Myocardial infarction, asymptomatic pericardial effusions are common. Rarely-pericarditis, constrictive pericarditis.
Myocarditis, coronary vasculitis, valvular dx, and conduction defects.
• Ocular involvement
Keratoconjunctivitis siccais common in RA and is often the initial manifestation of secondary Sjögren syndrome. The eye
may also have episcleritis, uveitis, and nodular scleritis that may lead to scleromalacia
• Hematologic manifestation
anemia, thrombocytosis, and eosinophilia. Leukopenia in patients with Felty’s syndrome (splenomegaly, neutropenia and
thrombocytopenia).
• Neurologic manifestations
nerve entrapment, carpal tunnel syndrome, mononeuritis multiplex, and cervical myelopathy.
Rheumatoid nodule
•These are small subcutaneous nodules present
at the extensor surfaces of hand, wrist, elbow
and back in rheumatoid arthritis patients.
LABORATORY FINDINGS
• ↑ erythrocyte sedimentation rate (ESR)
• ↑ C-reactive protein (CRP)
• (+) Rheumatoid factor (RF)
• (+) Anticyclic citrullinated peptide (anti-CCP)
• Synovial fluid: turbid with many leukocytes
• Radiographic imaging
ARA Diagnostic Criteria
RA Classification Criteria
• Collaboration of the American College of
Rheumatology (ACR) and the European League
Against Rheumatism (EULAR)
• 4 different domains in scoring algorithm
• Aimed at newly presenting patients who:
– Have ≥ 1 joint with clinical synovitis
– Synovitis is not better explained by another disease
> 6/10 for classification of definite RA SCORE
Joint involvement 1 large joint 0
2-10 large joints 1
1-3 small joints 2
4-10 small joints 3
> 10 joints (at least one small) 5
Serology (> 1) Negative RF and negative anti-CCP Abs 0
Low-positive RF or low-positive anti-CCP Abs 2
High-positive RF or high-positive anti-CCP Abs 3
Acute phase reactants Normal ESR and normal CRP 0
Abnormal ESR or abnormal CRP 1
Symptom duration < 6 weeks 0
> 6 weeks 1
Disease severity
● Mild disease
•Arthralgias
•>3 inflamed joints
•Mild functional limitation
•Minimally elevated ESR & CRP
•No erosions/cartilage loss
•No extraarticular disease i.e. anemia
● Moderate Disease
•6-20 Inflamed joints
•Moderate functional limitation
•Elevated ESR/CRP
•Radiographic evidence of
inflammation
•No extraarticular disease
● Severe Disease
•>20 persistently inflamed joints
•Rapid decline in functional capacity
•Radiographic evidence of rapid progession of bony erosions and
loss of cartilage
•Extraarticular disease:
• AOCD, Hypoalbuminemia
PREDICTORS OF WORSE
• Older age
OUTCOME
• Female gender
• Genotype (HLA-DRB1)
• Worse physical functioning
• Cigarette smoking
PROGNOSTIC
FACTORS
• Functional limitation
• Extraarticular disease
• RF and/or anti-CCP antibody positivity
• Bony erosions on radiographic imaging
• Management of comorbidities
Disease duration and activity are also important when assessing prognosis
CASE #1
• MJ is a 36 year old female who presents to her PCP c/o joint
pain in her hands and wrists (~6 joints) that has persisted for
the past 2 months. She receives little relief from OTC
NSAIDs, and on examination, the joints on both hands appear
red and swollen. Laboratory testing shows positive RF and
anti-CCP antibodies (high-positive) and ↑ ESR.
TREATMENT
Treatment Goals
Management
Nonpharmacologic Treatment
• Smoking cessation
• Rest
• Physical therapy, occupational therapy
• Weight loss
• Surgery
• Tenosynovectomy, tendon repair, joint replacement
1. NSAIDs
• Anti-inflammatory, analgesic effects
• Inhibition of COX-1 and COX-2
• No disease modification
• Common products
– Celeboxib, ibuprofen, naproxen
2. Corticosteroids
• Controls RA symptoms quickly
• Potent inhibitory effects of pro-inflammatory cytokines some
disease modifying activity (anti-erosive)
• Useful for early disease before DMARD activity present, acute
flares, combination maintenance therapy
• Long-term adverse events limit use
• Systemic
Proposed
– Prednisone Dose per day in
Dosing
prednisone equivalents
– Prednisolone Nomenclature
• Methotrexate
• Leflunomide
• Hydroxychloroquine
• Sulfasalazine
• Minocycline
• Methotrexate (MTX)
• Mechanism of Action
dihydrofolate reductase inhibitor
Folate antimetabolite inhibits purine synthesis
May inhibit cytokine production and stimulate adenosine release
Initial therapy of choice: most likely to induce long-term response
Dose: 7.5-15mg PO once weekly
Onset: 2-3 weeks
• Dosing and Administration
Initiation: 7.5 mg once per week or 2.5 mg bid three days per week, titrate up by 2.5 mg every 2weeks
Consider parenteral admin with doses ≥ 15 mg
Combine with folic acid supplementation
MINOCYCLINE
Out of the non-biologic DMARDs, what is the best option for initial therapy
for MJ?
SUMMARY: DMARDs
DRUG DOSE MONITORING
PO: 200-300mg BID x 1-2 months, then can ↓ • Baseline eye exam
Hydroxychloroquine
to 200mg daily or BID • Ophthalmoscopy q9-12 months
• Baseline CBC
Sulfasalazine PO: 500mg BID, then ↑ to 1000mg BID • CBC weekly x 1 month, then q1-2
months
Drug Targets:
•TNF α
•IL-1
•IL-6
•B cells
•JAK
• Genetically engineered protein molecules that target pro-
inflammatory cytokines or lymphocytes
• Not considered first line therapy
● High disease activity with poor prognostic factors
• May be effective when non-biologic DMARDs have failed
• Expensive
TNF α INHIBITORS
• Inactivate TNF α, preventing interaction with receptor and inhibiting immune
cell activation
• Increased infection risk
● Tuberculosis: must test prior to initiation
● Avoid live vaccines
• Multiple sclerosis-like illness
• Increased risk for lymphoma and other cancers
• Contraindication: NYHA class III-IV heart failure
DRUG DOSE ADVERSE COMMENTS
REACTIONS
Infliximab IV: 3 mg/kg at 0, 2, & 6 Infusion reactions: flu- Given with MTX to prevent
weeks, then q8 weeks like symptoms Ab formation (superior to
monotherapy)
Etanercept SQ: 50mg once weekly Local injection-site • Avoid in MS
OR 25mg two times a reactions Preferred with HCV
week May slow erosive
disease > MTX
Adalimumab SQ: 40mg every 2 weeks Local injection-site Less antigenic than
reactions infliximab
Golimumab SQ: 50mg once a month Local injection site Given in combination with
IV: 2 mg/kg at 0 & 4 reactions MTX
weeks, then q8 weeks
Certolizumab SQ: 200mg at 0, 2, & 4 • Local injection site Given as monotherapy or
weeks, then every 2 reactions in combination with MTX
weeks Nausea
• Abatacept
• Binds to antigen-presenting cells, preventing interaction with T cells and subsequent T cell activation
• For patients who have failed MTX therapy or TNF α inhibitors
● Response rate of 50% in clinical trials
● Weight-based dosing: IV infusion at 0, 2, & 4 weeks, then q4 weeks
● < 60kg: 500mg
● 60-100kg: 750mg
● > 100kg: 1000mg
● Alternative: 125mg SQ weekly
● Adverse reactions: headache, nausea, nasopharyngitis, infection, infusion reactions
INTERLEUKIN-6 INHIBITOR
Tocilizumab
• IL-6 receptor antagonist, reducing production of
cytokines and acute phase reactants
• For patients who have failed MTX therapy or TNF α
inhibitors
• Can be as monotherapy or in combination with MTX
JANUS KINASE (JAK) INHIBITOR
Inhibits cytokine production, which is integral to lymphocyte function
Place in RA therapy unclear
• Xeljanz (tofacitinib)
• FDA approved in 2012
● Moderate to severe RA refractory to MTX
• Versus placebo and MTX: significantly less symptoms and
improved physical function
• Dose: 5mg PO BID
COMBINATION
•
THERAPY
Typically effective when monotherapy fails
• May be appropriate initially in moderate to high disease activity
• Biologics in combination with MTX may be more effective
than biologic monotherapy
• Combination therapy with > one biologic is not recommended
• JF is a 63 year old female who was recently diagnosed with RA. PMH
significant for osteoporosis. She reports difficulty performing her daily
activities and painful, swollen joints that keep her up at night. She has high
disease activity with the presence of bony erosions on imaging.
The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen
joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment,
functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte
sedimentation rate or C-reactive protein (CRP).
ACR50 and ACR70 are the same instruments with improvement levels defined as 50% and 70% respectively versus 20% for
ACR20.